tard-15821: klinik araştırma magnezyum sülfatın...

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TARD-15821: Klinik Araştırma

Magnezyum sülfatın obstetrik hastalarda anestezi derinliği

üzerine etkisi

Amaç: Çalışmadaki öncelikli hipotezimiz, magnezyumun genel anesteziye bir yardımcı gibi davranarak anestezi derinliğini arttırabildiğidir. İkincil hipotezimiz, magnezyum infüzyonunun sezeryan seksiyo 5 operasyonu sonrası ağrıyı azaltabildiğidir. Yöntemler: Genel anestezi altında sezeryan seksiyo yapılması planlanan hastalar randomize olarak dört

gruba ayrıldı. İndüksiyon sonrası idame amacıyla Grup S’de sevofluran, Grup D’de desfluran kullanıldı (kontrol grupları). Grup S-M ve Grup D-M’de, sırasıyla sevofluran ve desfluran anestezisiyle beraber

magnezyum infüzyonu başlandı (çalışma grupları). İdame boyunca inhaler gazların minimum alveolar 10 konsantrasyonları sabit tutuldu. Bispectral index skorları (BIS), hemodinamik parametreler, train of four (TOF) değerleri ve postoperatif vizüel analog skalası değerleri kaydedildi. Tüm hastalar farkındalık

açısından değerlendirildi ve postoperatif 5 yıl boyunca takip edildi. Bulgular: Çalışmaya toplamda 100 hasta dahil edildi. BIS skorları kontrol gruplarında operasyon boyunca

belirgin biçimde yüksekti (p<0.001). Hemodinamk parametrelerde belirgin bir fark elde edilmedi. Tüm 15 zaman noktalarında kontrol gruplarının TOF değerleri daha yüksekti (p<0.05). VAS değerleri çalışma gruplarında belirgin biçimde düşüktü (p<0.05). Hastaların hiçbiri genel anestezi altında farkındalık

yaşamadı. Sonuç: Magnezyum infüzyonu belirgin biçimde daha düşük BIS değerleri ve postoperatif VAS skorları

sağlamıştır. Magnezyumun sezeryan seksiyo hastalarında genel anesteziye yardımcı olarak faydalı 20 olabileceğine inanmaktayız.

Anahtar Kelimeler: Anestezi derinliği, bi-spectral indeks, farkındalık, genel anestezi, magnezyum, postoperatif ağrı

Effect of magnesium sulphate on anesthetic depth of obstetric 25

patients

Objective: In this study, our primary hypothesis is magnesium can increase the depth of anesthesia by acting as an adjuvant to general anesthesia. Our secondary hypothesis is magnesium infusion can reduce

postoperative pain after caesarean section. Methods: The patients scheduled for caesarean section under general anesthesia were divided into four 30 groups randomly. After induction, sevoflurane was used for maintenance in Group S and desflurane in Group D (control groups). At Group S-M and Group D-M (study groups), magnesium infusion was started

with sevoflurane and desflurane anesthesia respectively. Minimum alveolar concentration of inhaler

anesthetic agents were kept constant throughout the maintenance. Bispectral index scores (BIS), hemodynamic parameters, train of four values (TOF) and postoperative visual analogue scale (VAS) 35 values were recorded. All of the patients were evaluated for awareness and followed up for five years postoperatively.

Results: A total of 100 patients were included in the study. BIS values were significantly higher in control

groups throughout the operation (p < 0.001). No significant difference was obtained at hemodynamic parameters. At all time points, TOF values of control groups were higher ( p < 0.05). VAS values were 40 significantly lower in study groups ( p < 0.05). None of the patients had awareness under general anesthesia.

Conclusion: Magnesium infusion provided significantly lower intraoperative BIS values and lower

postoperative VAS scores. We believe that magnesium can be useful as an adjuvant to general anesthesia in cesarean section patients. 45

Key words: Anesthetic depth, bi-spectral index, awareness, general anesthesia, magnesium,

postoperative pain

Ref.No: TARD-15821 (2)

Makale Grubu: Genel Anestezi 50 Makale Türü: Klinik Araştırma

Kayıt Tarihi: 08.09.2016 22:30:47

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Revised Files (1) Tam Metin 55 maintext Kayıt Tarihi: 03.10.2017 03:45:32

INTRODUCTION 60

Magnesium has widely been used in anesthetic management in the recent years. It was shown

to attenuate stress response to endotracheal intubation, preserving favorable hemodynamics,

block acetylcholine discharge from neuromuscular junction and potentiate the effect of non-

depolarizing neuromuscular blockers. Recently magnesium sulphate was reported to reduce

anaesthetic requirements, shorten anaesthetic induction with propofol and diminishe total 65

postoperative analgesic consumption with no adverse maternal or neonatal effects [1-3]. It has

potential analgesic and sedative properties, therefore it may be used as an adjuvant during general

anesthesia [4].

In the current literature, there are studies examining the effects of magnesium on the anesthetic

agent doses needed to keep bi-spectral index (BIS) values within a fixed range, however untill now 70

only one single pediatric study evaluated the influence of intraoperative magnesium on BIS values

while keeping other intraoperative variables (such as operation type and end-tidal anesthetic

consantration) almost constant. But in this recent study, depth of anesthesia was evaluated only by

intraoperative BIS values [5].

The term “awareness” under anesthesia is used in literature as the wakening of brain by a stimulant 75

under general anesthesia and storing this information in order to recall it in the future [6]. Although

most of the patients experienced awareness may seem to have no complaint in the long time period

postoperatively [7], symptoms like nightmares, daytime anxiety and flashbacks can be seen and in

some cases, even patients may develop posttraumatic stress disorder [7, 8].

Although over the last 20 years, there has been a large increase in the proportion of caesarean 80

section performed under regional anaesthesia, in emergency situations or when there is a

contraindication for regional anesthesia or in the situation of patient’s refusal, general anesthesia is


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applied [9]. Therefore general anesthesia is still frequently performed for caesarean sections in

some clinics. As low doses of general anaesthetic agents have traditionally been used in caesarean

sections, obstetric patients are reported to have a higher incidence of intraoperative awareness than 85

other surgical patients, especially during the period before delivery [10].

In this study our primary hypothesis is magnesium can increase the depth of anesthesia by acting as

an adjuvant to general anesthesia in obstetric patients. We aimed to assess this effect by monitoring

bispectral index scores and incidence of awareness. Our secondary hypothesis is magnesium

infusion can reduce postoperative pain after caesarean section. 90

95

100

105

MATERIAL AND METHOD

After receiving hospital Clinical Trials Local Ethic Committee approval (reference Number: LUT-

10/60) and patients’ informed consents, 100 patients (American society of anesthesiologists status I-

II and between 17-41 years old) undergoing cesarean section with general anesthesia were included 110

in this prospective randomized controlled study. The study was conducted in accordance with the

Helsinki declaration in Ankara Hacettepe University Hospital between 2010-2011 and patient

follow-up has been continued untill 2016 via phone calls. Patients with known history of

magnesium sulphate hypersensivity, hypermagnesemia, any degree of heart block, hypertension,

diabetus mellitus, preterm or multiple pregnancy, preoperative fetal distress or other medical 115


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conditions were excluded from the study. In the operating room, electrocardiogram, non invasive

blood pressure, peripheral oxygen saturation, train of four (TOF) (Datex-Ohmeda N-NMT Sensors)

and BIS (Datex-Ohmeda S/5TM) measurements were monitored. Patients were randomized into

four groups by using a computer-generated randomization schedule and each group included 25

patients. The study drug solutions were prepared into 20-mL identical syringes for bolus doses and 120

500-mL serum physiologic solutions for intraoperative infusions and labeled by an anesthetist who

did not participate in the study. The investigators and patients were blinded to group allocation. The

first and the second groups were planed to receive sevoflurane and desflurane as inhalation

anesthetic agent respectively. They were planed to receive serum physiologic in 20-mL syringes and

serum physiologic as infusion solution (Group S and D). These two groups were “control groups” 125

of the study. In the third and fourth groups, patients were planed to receive sevoflurane and

desflurane as inhalation anesthetic agent respectively. They were planed to receive 30 mg kg ֿ ֿ ¹

magnesium sulfate in 20-mL syringes and magnesium sulfate plus serum physiologic as infusion

solution (Group S-M and D-M). These two groups were our “study groups”. So there would be

totally 50 patients in control groups and 50 patients in the study groups. 130

Induction was performed with 2-3 mg kg ֿ ¹ i.v propofol and 0.6 mg kg ֿ ֿ i.v rocronium bromide in

all groups. After induction, in groups S-M and D-M, 30 mg kg ֿ ¹ i.v magnesium sulfate was

applied as bolus in 15-20 seconds and then 10 mg kg ֿ ֿ hour ֿ ¹ magnesium sulfate infusion in 500-

mL serum physiologic solution was started.

At the maintenance of anesthesia 2% end-tidal sevoflurane and 4 lt min ֿ ֿ ֿ ¹ 40% O2-60% N2O 135

were used in group S and group S-M, and 6% end-tidal desflurane and 4 lt min ֿ ¹ 40% O2-60%

N2O were used in group D and group D-M. When heart rate or blood pressure increased more than

20% of baseline values, fentanyl 1 mcg kg ֿ ֿ ¹ was applied intravenously while minimum alveolar

concentration (MAC) remained constant. In all groups BIS values, mean arterial pressure (MAP)

and heart rate of the patients were recorded before induction, right after induction and at five minute 140

intervals throughout the operation. TOF measurement started after induction and continues with five


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minute intervals throughout the operation. Intraoperative opioid requirement was recorded

following induction and throughout the operation. For postoperative analgesia, 1000 mg

paracetamol was applied intravenously 15 minutes before the end of the surgery and 75 mg

diclofenac sodium was applied at every 8 hours in the ward. When Visual Analogue Scale (VAS) 145

scores were 4 or more, tramadol 1 mg kg ֿ ¹ i.v was applied as rescue analgesic. Patients were

evaluated at the postoperative 1st , 2nd and 24th hours by VAS.

In order to evaluate anesthesia depth in a more objective manner, patients were also assessed for

awareness under general anesthesia. For this purpose, following anesthesia induction, a text chosen

with the consultancy of Hacettepe University Medical Faculty Psychiatry Department was listened 150

to all patients via earphones. This text was a story included in the “Wechsler Memory Scale” used

for neurophysiological examination of the patients and there were 24 key words in this single line

text [11]. Similar to previous studies [12, 13], all patients were questioned at postoperative 1st, 6th,

24th hours, at the end of the 1st month by the same anesthesiogist. As an addition to previous studies,

we interviewed with the patients at the end of the first, second, third, fourth and fifth year in order 155

to evaluate long term effects of general anesthesia. First all patients were given some clues about

the story and then they were asked whether if they recalled anything about the text or not. Besides

Wechsler Memory Scale, questions from “Modified Brice interviews” which is still accepted as the

gold-standart for postoperative awareness screening were also asked [14]. The interview is

consisted of five simple questions which were first defined by Brice et al. [15] and then modified by 160

Moerman et al. [16]. These questions are listed as – “1) What is the last thing you remember before

sleeping? 2) What is the first thing you remember at awaking after the surgery? 3) Do you

remember anything in between? 4) Did you see any dreams? 5) What was the most disturbing thing

you remember about the operation and anesthesia?.

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170

175

STATISTICAL ANALYSIS

Calculation of sample size was based on previous investigations conducted about the effects of Mg

sulphate on BIS values and propofol consumption. Assuming α error = 0.05 (two-tailed) and β

error = 0.1. sample size of totally 45 patients, allocated into one group, will have a power of 90 % 180

to determine an assumed clinically significant difference of 5 % (effect size d = 0.6) between the

paired measurements of BIS value in groups with and without magnesium infusion. The sample size

was calculated using Power Analysis and Sample Size 12 software (NCSS, Kaysville, UT, USA).

The statistical anaylsis was made by using the Statistical Package for Social Science, version 17.0

(SPSS Inc., Chicago, IL). All demographic datas and perioperative periods were evaluated with One 185

Way Variance Analysis. Turkey-HSD test was used for the multiple comparison between groups.

For evaluation of VAS values non-parametric Kruskal-Wallis test was performed. Exact chi-square

test was used to compare additional analgesic need, dreaming, remembering and recalling the story.

“P < 0,05” was accepted as statistically significant and all datas was defined as “mean±SD”.

190

195

200

RESULTS

A hundred and twenty patients were included into the study. Two of the patients were excluded due

to intraoperative allergic symptoms. Six patients declined to participitate in the study during their


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follow-up in the postoperative period and twelve patients were excluded due to intraoperative 205

techniqual faults. The demographic variables and surgical characteristics of the remaining 100

patients were similar (Table 1).

For analysis of BIS values, five different time-points were chosen; before induction (BIS 0), 5

minutes after the induction (BIS 5), total operation median time (BIS Median) and end of the

operation (BIS End) (Table 2). 210

BIS values before the induction were similar in all groups (p > 0.05) whereas values at BIS 5 were

significantly higher in the sevoflurane group (p < 0.001).

At the BIS Median point; BIS values in control groups were statistically significantly higher than

the study groups ( p < 0.001), while Group S and Group D were similar to each other ( p = 0.519).

Likewise BIS End values of control groups were significantly higher than study groups ( p < 0.001), 215

while Group S and Group D were similar to each other (p = 0.781). There was no statistically

significant difference amoung study groups ( p = 0.737). BIS values measured in each group

throughout the operation is shown in Figure 1.

There was no significant difference at MAP and heart rate between the groups throughout the

operation ( p > 0.05) (Table 3). 220

At all time points, TOF values of group S and D were found to be higher than study groups. There

was no significant difference between the groups S-M and D-M or between control groups at any

time-point (Table 4).

225

Postoperative pain was questioned at 1st, 2nd and 24th hour. VAS scores in all time points were

significantly lower in study groups (p < 0.05). VAS scores of Group S and Groups D were similar,

and groups S-M and D-M were similar to each other (Table 5).

During the interviews performed at the end of 1st, 6th and 24th hour, one patient in group S, two in

group D and one in group D-M reported to have dream intraoperatively. They stated that their 230

dreams were not related to their surgeries. At the end of the first month, same four patients reported

that they dreamed intraoperatively but couldn’t remember anything about the content of their


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dreams. This difference amoung groups was not statistically significant (p = 0.9) (Table 6).

At the end of the first and second years we managed to interview with all patients and non of them

could remember anything new. At the end of the third, fouth and fifth years we couldn’t contact 235

with two patients in group S and three patients in each group S-M and group D-M. None of the

patients reported to hear any sound during the operation nor remember anything. None of the

patients could give a significant answer to the questions of Modified Brice interviews by means of

intraoperative awareness. Likewise, none of the patients could remember the story played through

earphones, or find any of the key words. None of the patients had any signs of posttraumatic stress 240

disorder meanwhile.

245

250 DISCUSSION

In the current study, BIS scores were significantly lower in groups with magnesium infusion, while

none of the patients had awareness under general anesthesia. Postoperative VAS scores were

significantly lower in groups with magnesium infusion. There was no significant difference at

hemodynamic parameters. But TOF values were significantly lower in groups with magnesium 255

infuion.

In general practice, BIS is accepted as a voluable monitor for depth of anesthesia both in adult and

pediatric patients. When the underlying mechanism of general anesthesia is considered, hypnosis as

a single component of anesthesia can not be used to define overall “anesthetic depth” [17], however

the hypnotic depth is known to be the primary endpoint of anesthesia and it has become the focus of 260

contemporary depth of anesthesia monitoring [18]. Therefore we evaluated the central effect of

magnesium by using BIS monitoring. In the literature, there are several studies which have


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evaluated the effect of intraoperative magnesium on intravenous or inhaled anesthetic doses, opioid

demands or muscle relaxant needs to keep BIS values between 40-60. However, Amer et al.

recently claimed that BIS values between 40-60 may be considered a relatively wide range to 265

objectively evaluate the effect of magnesium on anesthetic requirements. In their study, BIS was

used as the single monitoring and similar to the current study, BIS values were significantly lower

in magnesium group [5]. On the other hand, we have followed up the patients for five years and

performed interviews to evaluate “awareness” experience under general anesthesia. In other words,

we examined the central effect of magnesium in a long-term period beside it’s short term, 270

intraoperative effects.

Awareness under general anesthesia is often experienced due to inadequate levels of anesthesia

[19]. It’s been reported in the literature that serious psycological problems which leads to

posttraumatic stress disorder may occur during long-term follow up of these patients [6]. Today

intraoperative awareness is mostly observed when opioids and benzodiazepines or weak anesthetics 275

like nitrous oxide are used seperately or together. Contrary to this, inhalation anesthethics like

sevoflurane, desflurane, isoflurane and potent intravenous anesthetics used in proper concentrations

are believed to prevent intraoperative perception succesfully [20]. However, there are plenty of

intraopertive awareness cases experienced with inhalation anesthetics in the literature [21, 22]. In

the light of these informations, we suggested that adding an adjuvant agent to general anesthesia 280

might have helped to increase depth of anesthesia and prevent intraoperative awareness. We

prefered to add magnesium infusion to general anesthesia provided by sevoflurane or desflurane

anesthetics and none of our patients experienced awareness. Dreaming which is believed to be

related with awareness was detected at four patients, but when we compared the groups, there was

no statistically significant difference. Awareness under general anesthesia is a rare complication 285

seen between 0.1%-0.2% of all patients [6]. However, some publications reported that these

numbers can rise upto 7-28% in obstetric surgeries [6, 23]. Although the current study was held

with obstetric patients, no one reported to experience awareness. The most likely reason is our


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sample size may lack to detect an awareness case. Secondly, constant and reasonable MAC values

maintaned throughout the operation probably prevented awareness under general anesthesia. Beside 290

these, fentanyl was applied to the patients when hemodynamic parameters incresed more than %20

of baseline values.

In the study of Lee et al, different dosages of magnesium were compared with control group and it

was shown that BIS values were significantly lower in the groups with magnesium infusion [24]. In

the current study, BIS values were also significantly lower in the groups with magnesium infusion 295

throughout the operation. This result supports our suggestion about magnesium being a good

advujant to general anesthesia. Beside this, BIS values of the groups with magnesium infusion

didn’t differ significantly. This brings the idea that magnesium may deepen the level of anesthesia

with regardless of type of inhalated anesthetic agent. On the other hand, when we look at the non-

magnesium groups; BIS values in the 5th minute after induction was higher in sevolfurane group 300

than desflurane group. According to previous studies performed with similar inhalation anesthetics,

this difference between sevoflurane and desflurane is not suprising. It is known that different

inhalation anesthetics given at the end-tidal concentration levels providing same potency can result

in different BIS values of patients [25]. Jellish et al. compared sevoflurane and desflurane and

reported that BIS values were significantly lower in the desflurane group [26]. 305

The analgesic effect mechanism of magnesium sulfate has not been shown clearly yet, but

inhibition of calcium channels and N-methyl-D-aspartate receptors are believed to have an

important role [27]. In previous studies, bolus dosage of magnesium was shown to significantly

reduce additional analgesic requirement [28]. However in the current study, intraoperative fentanyl

consumption didn’t significantly differ between groups. The most possible reason is the difference 310

between methodologies of the studies. In the study of Gupta et al., fentanyl was applied in order to

keep BIS values between 40-60. On the other hand, we applied fentanyl according to hemodynamic

changes. As there was no significant difference in MAP and heart rate of the patients, no significant

difference was found in fentanyl consumption.


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In the literature, several studies have reported magnesium sulphate infusion to reduce postoperative 315

pain. Recently Mireskandari et al. have evaluated the effect of preoperatively induced magnesium

sulphate on postoperative pain in obstetric patients. They reported that intravenous bolus

magnesium sulphate prior to induction of general anesthesia could reduce postoperative VAS and

had sparing effects on morphine consumption during first 24 hours [29]. Similarly, VAS scores of

magnesium groups were significantly lower at all time points in our study. On the other hand, 320

Frassanito et al. have studied the effect of intravenous magnesium infusion on postoperative pain of

patients after total knee arthroplasty performed under spinal anesthesia. They couldn’t find any

significant difference at postoperative pain and analgesic consumption after intravenous magnesium

sulphate infusion [30]. Nowadays magnesium is in the focus of studies analyzing post operative

inflammation. It was recently reported to significantly reduce postoperative sore throat related to 325

endotracheal intubation [31]. Although the exact mechanism is not known, the attenuation effect of

magnesium on inflammatory response to surgery may also play a role to lower postoperative pain.

The major limitation of our study is the relatively small sample size. The power analyzis was

calculated in order to obtaine a significant difference between the paired measurements of BIS

value, so the calculated patient number was probably insufficent to detect an awareness case. In 330

order to get more objective data on awareness under general anesthesia, it’s necessary to perform

studies with larger number of patients but nowadays it’s becoming harder due to increased ratios of

regional anesthesia at cesarean sections.

335

CONCLUSION

In this study, magnesium infusion provided significantly lower intraoperative BIS values and lower

postoperative VAS scores. We believe that magnesium can be useful as an adjuvant to general 340

anesthesia in cesarean section patients. Larger number of sample size is needed to properly assess


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awareness under general anesthesia.

345

Acknowledgements

We are grateful to Prof Dr Başaran Demir from Hacettepe University Medical Faculty Department of Psychiatry for his consultancy at awareness assessment. 350

355

360

365

370

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29. Mireskandari SM, Pestei K, Hajipour A, Jafarzadeh A, Samadi S, Nabavian O: Effects of preoperative magnesium sulphate on post-cesarean pain, a placebo controlled double blind study. Journal of 440 family & reproductive health 2015, 9(1):29-33.


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30. Frassanito L, Messina A, Vergari A, Colombo D, Chierichini A, Della Corte F, Navalesi P, Antonelli M: Intravenous infusion of magnesium sulfate and postoperative analgesia in total knee arthroplasty. Minerva anestesiologica 2015, 81(11):1184-1191.

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450

There is no conflict of interest.

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Kaynaklar 460 References

Kayıt Tarihi: 03.10.2017 03:46:34

REFERENCES 465

1. Altan A, Turgut N, Yildiz F, Turkmen A, Ustun H: Effects of magnesium sulphate and clonidine on propofol consumption, haemodynamics and postoperative recovery. British journal of anaesthesia 2005, 94(4):438-441.

2. Gupta K, Vohra V, Sood J: The role of magnesium as an adjuvant during general anaesthesia. 470 Anaesthesia 2006, 61(11):1058-1063.

3. Kutlesic MS, Kutlesic RM, Mostic-Ilic T: Magnesium in obstetric anesthesia and intensive care. Journal of anesthesia 2017, 31(1):127-139.

4. Barbosa FT, Barbosa LT, Juca MJ, Cunha RM: Applications of magnesium sulfate in obstetrics and anesthesia. Rev Bras Anestesiol 2010, 60(1):104-110. 475

5. Amer MM, Abdelaal Ahmed Mahmoud A, Abdelrahman Mohammed MK, Elsharawy AM, Ahmed DA, Farag EM: Effect of magnesium sulphate on bi-spectral index (BIS) values during general anesthesia in children. BMC anesthesiology 2015, 15:126.

6. Ghoneim MM, Block RI, Haffarnan M, Mathews MJ: Awareness during anesthesia: risk factors, causes and sequelae: a review of reported cases in the literature. Anesthesia and analgesia 2009, 480 108(2):527-535.

7. Lopez U, Habre W, Van der Linden M, Iselin-Chaves IA: Intra-operative awareness in children and post-traumatic stress disorder. Anaesthesia 2008, 63(5):474-481.

8. Osterman JE, Hopper J, Heran WJ, Keane TM, van der Kolk BA: Awareness under anesthesia and the development of posttraumatic stress disorder. Gen Hosp Psychiatry 2001, 23(4):198-204. 485

9. Campbell J, Sultan P: Regional anaesthesia for caesarean section: a choice of three techniques. Br J Hosp Med (Lond) 2009, 70(10):605.

10. Sebel PS, Bowdle TA, Ghoneim MM, Rampil IJ, Padilla RE, Gan TJ, Domino KB: The incidence of awareness during anesthesia: a multicenter United States study. Anesth Analg 2004, 99(3):833-839, table of contents. 490

11. Shaygannejad V, Janghorbani M, Ashtari F, Zanjani HA, Zakizade N: Effects of rivastigmine on memory and cognition in multiple sclerosis. Can J Neurol Sci 2008, 35(4):476-481.

12. Myles PS, Leslie K, McNeil J, Forbes A, Chan MT: Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004, 363(9423):1757-1763.

13. Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M: Effect of epidural 495 dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilation. Acta Anaesthesiol Scand 2010, 54(6):703-709.

14. Sneyd JR, Mathews DM: Memory and awareness during anaesthesia. Br J Anaesth 2008, 100(6):742-744.

15. Brice DD, Hetherington RR, Utting JE: A simple study of awareness and dreaming during 500 anaesthesia. Br J Anaesth 1970, 42(6):535-542.

16. Moerman N, Bonke B, Oosting J: Awareness and recall during general anesthesia. Facts and feelings. Anesthesiology 1993, 79(3):454-464.

17. Campagna JA, Miller KW, Forman SA: Mechanisms of actions of inhaled anesthetics. The New England journal of medicine 2003, 348(21):2110-2124. 505

18. Bruhn J, Myles PS, Sneyd R, Struys MM: Depth of anaesthesia monitoring: what's available, what's validated and what's next? British journal of anaesthesia 2006, 97(1):85-94.

19. Ghoneim MM: Awareness during anesthesia. Anesthesiology 2000, 92(2):597-602. 20. Guler T: İntraoperatif Uyanıklık. Türk Anesteziyoloji ve Reanimasyon Derneği Dergisi 2009,

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21. Kino A KR, Wakamatsu T, Hashiguchi M, Nakamura K: Awareness during anesthesia with sevoflurane: a case report. Masui The Japanese journal of anesthesiology 2006, 55(10):1250-1252.

22. Kino A NK: Awareness during general anesthesia for head and neck surgery--a case report. Masui The Japanese journal of anesthesiology 2011, 60(2):241-243.

23. Paech MJ, Scott KL, Clavisi O, Chua S, McDonnell N, Group AT: A prospective study of awareness 515 and recall associated with general anaesthesia for caesarean section. International journal of obstetric anesthesia 2008, 17(4):298-303.

24. Lee DH, Kwon IC: Magnesium sulphate has beneficial effects as an adjuvant during general anaesthesia for Caesarean section. Br J Anaesth 2009, 103(6):861-866.

25. Samarkandi AH: The bispectral index system in pediatrics--is it related to the end-tidal 520 concentration of inhalation anesthetics? Middle East J Anesthesiol 2006, 18(4):769-778.

26. Jellish WS, Owen K, Edelstein S, Fluder E, Leonetti JP: Standard anesthetic technique for middle ear surgical procedures: a comparison of desflurane and sevoflurane. Otolaryngol Head Neck Surg 2005, 133(2):269-274.

27. Miranda HF, Bustamante D, Kramer V, Pelissier T, Saavedra H, Paeile C, Fernandez E, Pinardi G: 525 Antinociceptive effects of Ca2+ channel blockers. Eur J Pharmacol 1992, 217(2-3):137-141.

28. Gupta SD, Mitra K, Mukherjee M, Roy S, Sarkar A, Kundu S, Goswami A, Sarkar UN, Sanki P, Mitra R: Effect of magnesium infusion on thoracic epidural analgesia. Saudi journal of anaesthesia 2011, 5(1):55-61.

29. Mireskandari SM, Pestei K, Hajipour A, Jafarzadeh A, Samadi S, Nabavian O: Effects of preoperative 530 magnesium sulphate on post-cesarean pain, a placebo controlled double blind study. Journal of family & reproductive health 2015, 9(1):29-33.

30. Frassanito L, Messina A, Vergari A, Colombo D, Chierichini A, Della Corte F, Navalesi P, Antonelli M: Intravenous infusion of magnesium sulfate and postoperative analgesia in total knee arthroplasty. Minerva anestesiologica 2015, 81(11):1184-1191. 535

31. Yadav M CN, Gopinath R: Effect of magnesium sulfate nebulization on the incidence of


540


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Tablolar Tables

Kayıt Tarihi: 03.10.2017 03:46:58

545 TABLES:

Table 1. Patient and Surgery Characteristics:

*Sevo: sevoflurane, des: desflurane, mg: magnesium sulphate

The patient characteristics and surgery characteristics were similar in each group. 550

555

560

565

570 Table 2. BIS Values at Different Time-Points Amoung Groups

BIS Sevo Des Sevo+Mg Des+Mg p

BIS 0 95.9±2.76 95.2±3.05 95.3±2.88 96.28±2.4 0.504

BIS 5 50.8±7.8 45.96±6.5 39.2±5.5 35.96±5.1 < 0.001

Sevo Sevo + Mg Des Des + Mg p

Age (Year) 29.7 ± 5.1 30.2 ± 5.8 30.2 ± 4.3 29.7 ± 4.78 0.976

Weight (kg) 73.4 ± 14.7 77.5 ± 11.8 79.9 ± 14.7 77.1 ± 14 0.415

Operation time

(min)

47.4 ± 11.19 44.8 ± 7.96 47.6 ± 10.7 41.4 ± 9.6 0.103


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BIS Med 55.6±6.08 52.6±7.1 40.9±7.4 41.1±9.78 < 0.001

BIS End 64.8±7.5 62.88±4.5 53.0±8.2 50.88±8.3 < 0.001

BIS: bispectral index score, sevo: sevoflurane, des: desflurane, mg: magnesium sulphate,

BIS 0: BIS value before induction, BIS 5: BIS value 5 minutes after induction,

BIS Med: BIS value at the medium point of operation, BIS End: BIS value at the end of the 575

operation

580

585

590

595

600

Table 3. Hemodynamic Parameters Amoung Groups


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HR

Sevo

Des

Sevo+M

g

Des+Mg

P

MAP

Sevo

Des Sevo+Mg Des+Mg P

0.Min 102 ±17.1 97.3±19.7 106±16.6 106.4±13.8 0.222 98±13.8 92.3±11.5 91.3±71. 91.4±14.8 0.165

5.Min 113.8±14 106±18.3

111.4±12.9 108.7±11.2 0.297 92.3±16.5 86.9±13 84.9±12 86.1±13.4 0.259

Med 91.5±14.4 88±16.9 96.7±18.3 89.2±13.4 0.229 83.8±12.9 83.2±10.6 84.9±12.5 83.2±14.5 0.962

End 93.8±14.8 89.9±16.4 96.4±14.1 89.2±10.2 0.257 88.1±15.6 82.8±11.6 83.4±12.5 85±12.3 0.486

HR: Heart Rate, MAP: Mean arterial pressure 605

610

615

620


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Table 4. TOF Values at Different Time-Points Amoung Groups

625 Sevo: sevoflurane, des: desflurane, mg: magnesium sulphate, TOF: Train of four TOF 5: TOF value 5 min after induction, TOF 10: TOF value 10 minutes after induction

TOF Med: TOF value at the medium point of operation, TOF End: TOF value at the end of the operation

630

635

640

TOF Sevo Des Sevo+Mg Des+Mg p

TOF 5 2.5±1.6 1.7±1.7 0.5±0.8 1±1.5 < 0.01

TOF 10 2.3±1.2 1.5±1.4

0.3±0.6 0.6±0.7 0.024

TOF Med 2.4±1.1 2.3±1.2 0.7±0.7 0.8±0.8 0.036

TOF End 3.8±0.4 3.9±0.2 2.8±1.1 2.5±1.2 0.01


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645

Table 5. VAS Scores at Different Time Points Amoung Groups

Sevo: sevoflurane, des: desflurane, mg: magnesium sulphate, SD: standart deviation, VAS1: VAS

score at postoperative first hour, VAS2: VAS score at postoperative second hour, VAS24: VAS score 650

at postoperative 24th hour

655

660

665

VAS Sevo Des Sevo+Mg Des+Mg p

VAS 1 8.1±0.9 8.1±0.8 7.1±0.6 7.1±0.6 < 0.01

VAS 2 5.1±0.6 4.8±0.8

3.5±0.6 3.5±0.6 0.024

VAS 24 4.0±0.6 3.8±0.7 3.0±0.6 03±0.4 0.036


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Table 6. Dreaming Amoung Groups At the End of the First Month

Dream Sevo Des Sevo+Mg Des+Mg p

Yes 1 2 0 1 0.9

No 24 23 25 4

670

675

680


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Resimler Figures

Kayıt Tarihi: 03.10.2017 03:47:38 685

Figure 1. BIS Values Measured in Different Time Points Among the Groups

Sevo; sevoflurane, des; desflurane, mg; magnesium sulphate, BIS; bispectral index 690


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Revizyon Notu Response

Kayıt Tarihi: 03.10.2017 03:49:00 695

RESPONSE TO THE REVIEWER COMMENTS:

Reviewer 1. 700

Comment 1. “Sample size may not be enough for this kind of study. Power analysis of the study should be

included in statistical analysis section. “

Answer 1. Sample size is not enough to detect an awareness case, but in the current study power analysis

was calculated to obtain a significant difference in BIS values between control and study groups. 705

The title of the study is changed and the following part is inserted to the statistical analysis:

“Calculation of sample size was based on previous investigations conducted about the effects of Mg


error = 0.1. sample size of totally 45 patients, allocated into one group, will have a power of 90 % 710



was calculated using Power Analysis and Sample Size 12 software (NCSS, Kaysville, UT, USA).

Comment 2. “Statistical significances (as * P values) must be included in tables and on figures.” 715

Answer 2. All of the tables are revised with “p” values.

Comment 3. “ Conclusion paragraph must be revised.”

720

Answer 3. Conclusion paragraph is revised as below:

“In this study, magnesium infusion provided significantly lower intraoperative BIS values and

lower postoperative VAS scores. We believe that magnesium can be useful as an adjuvant to general

anesthesia in cesarean section patients. Larger number of sample size is needed to properly assess 725

awareness under general anesthesia. “


/ 50


730

Reviewer 2.

Comment 1. “Power analysis? There are multiple endpoints but no power analysis. The proper

power analysis should be made for the main endpoints of this study.” 735

Answer 1. The power analysis of the study was calculated to obtaine a significant difference in BIS values

between control and study groups.

The primary end point of the study is changed and the following part is added to the statistical analysis:

“Calculation of sample size was based on previous investigations conducted about the effects of Mg 740


error = 0.1. sample size of totally 45 patients, allocated into one group, will have a power of 90 %



was calculated using Power Analysis and Sample Size 12 software (NCSS, Kaysville, UT, USA). 745

Comment 2. “Did MgSO4 administration lead to significant changes in the hemodynamic status

between groups?”

Answer 2. In our study magnesium sulphate had no significant effect between groups, so we didn’t 750

need to mention it in the text. But after the reviewer’s comment, we added the following sentence

and related table into the results section:

“There was no significant difference at MAP and heart rate between the groups throughout the

operation ( p > 0.05) (Table 3).”

755

Comment 3. “Was there any significant difference in duration of emergence, recovery and PACU

stay between groups?”

Answer 3. Regarding the TOF values, we inserted the following part and related table into the

result section: 760

“At all time points, TOF values of group S and D were found to be higher than study groups. There

was no significant difference between the groups S-M and D-M or between control groups at any

time-point (Table 4).”


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Unfortunatelly duration of emergence and recovery was not an end point of our study and we didn’t 765

collect data.

Comment 4. “ Mean VAS scores were above 4 in almost all patients until 1 hour after operations.

Ethically, the aim of postoperative analgesia should be keeping the pain scores below 3-4.

Additionally, there is no comment about the amount of the rescue analgesic. Did all the patients

receive only diclofenac 75 mg?” 770

Answer 4. Dear reviewer, VAS1 is the pain score of patients at the first evaluation. The rescue

analgesic (first step diclofenac 75 mg im, second step tramadol 1 mg/kg iv) was added at the end of

this first evaluation. So, VAS values were significantly lower in the second hour. The following

sentence is inserted into the methodology part: “For postoperative analgesia, 1000 mg paracetamol 775

was applied intravenously 15 minutes before the end of the surgery and 75 mg diclofenac sodium

was applied at every 8 hours in the ward. When Visual Analogue Scale (VAS) scores were 4 or

more, tramadol 1 mg kg ֿ ¹ i.v was applied as rescue analgesic.”

Although the data about resque analgesic was recorded, no significant difference was found. So, we

didn’t mention it in the text. 780

Comment 5. “Table 1: Is the duration of operation in Des+Mg Group 4,4±9,6 minutes (I think

44±9,6)

Answer 5. All of the tables are revised. The correct duration is 41.4 ±9.6 minutes.

785

Comment 6. “I wonder if all the patients in Table 4 received only a single dose fentanyl. If not, the

dose of fentanyl requirement between groups will be more important (may be significant).”

Answer 6. When needed, fentanyl was administered as 1 mcg/kg iv to very patients. As there was

no significant difference between groups, we deleted the part about intraoperative analgesic 790

requirements and the related table.

Comment 7. “The authors should discuss their results in terms of fentanyl consumption,

hemodynamic status, emergence-recovery time and postoperative analgesia with the recent studies

in which similar methodology used in adult patients underwent caesarean section under general 795

anaesthesia.”


/ 50


Answer 7. We dicussed fentanyl consumption and postoperative analgesia with some of the refered

studies. Some of the old references are replaced with latest ones.

800

Reviewer 3:

805

Comment 1. “I think that the sentence in P5 L 135 '' 3) Do you remember anything in

between?.''may be little confused. The sentence can be made more clear.”

Answer 1. Dear Editor, this sentence is a part of “Modified Brice interviews” which is still accepted

as the gold-standart for postoperative awareness screening. We didn’t make any difference in the 810

original questionarre.

Comment 2. “It would be better to add a table for awareness results.”

Answer 1. A table about dreaming insidence amoung groups is added to the Results section (Table 815

6). None of the patients could remember any words from Wechsler Memory Scale, so we didn’t

make any tables about that data.

Comment 3. “Why cesarean patients were evaluated for study? Does the gynecology clinic have an

indication for the use of magnesium?” 820

Answer 3. Both in the “Introduction” and “Discussion” sections, we tried to mention the

importance of obstetric surgery for awareness:

“As low doses of general anaesthetic agents have traditionally been used in caesarean sections, 825

obstetric patients are reported to have a higher incidence of intraoperative awareness than other

surgical patients, especially during the period before delivery [10].”

“Awareness under general anesthesia is a rare complication seen between 0.1%-0.2% of all patients

[6]. However, some publications reported that these numbers can rise upto 7-28% in obstetric

surgeries [6, 23].” 830

Although in obstetric intensive care, magnesium represents a first-choice medication in the


/ 50


treatment and prevention of eclamptic seizures, we didn’t allocate eclamptic patients into the

study.

Comment 4. “The sentence in P9 L 215; '' We believe that magnesium infusion in cesarean section

can be useful by reducing patients’ inoperative anesthetic and postoperative analgesic need and 835

prevent depressant effects on fetus.'' But, there is no clinical result about the fetus at article. How

accurate can be your result? If you have data with the fetus, you should add.”

Answer 4. The comment regarding the fetus is deleted from the text. Conclusion paragraph is

revised as below: 840

“In this study, magnesium infusion provided significantly lower intraoperative BIS values and

lower postoperative VAS scores. We believe that magnesium can be useful as an adjuvant to general

anesthesia in cesarean section patients. Larger number of sample size is needed to properly assess

awareness under general anesthesia. “ 845

850


/ 50


Original Files Tam Metin

Main TEXT awareness Kayıt Tarihi: 09.09.2016 11:15:12 855

INTRODUCTION

The term “awareness” under anesthesia is used in literature as the wakening of brain by a stimulant 860

under general anesthesia and storing this information in order to recall it in the future (1). Although

most of the patients experienced awareness may seem to have no complaint in the long time period

postoperatively (2), symptoms like nightmares, daytime anxiety and flashbacks can be seen and in

some cases, even patients may develop posttraumatic stress disorder (2, 3).

Over the last 20 years, there has been a large increase in the proportion of caesarean section 865

performed under regional anaesthesia. But in emergency situations, when there is a contraindication

for regional anesthesia or in the situation of patient’s refusal, general anesthesia is applied (4).

Therefore general anesthesia is still frequently prefered in some clinics.

Low concentrations of anaesthetic agents until delivery have traditionally been used for caesarean

section under general anesthesia to prevent uterine atony and neonatal respiratory depression. As a 870

result, obstetric patients have a higher incidence of intraoperative awareness than other surgical

patients, especially during the period before delivery (5).

Over the recent years, magnesium has been widely used in anesthesia management. It was reported

to regulate cardiovascular response by reducing cathecolamin release associated with tracheal

intubation, block acetylcholine discharge from neuromuscular junction and potentiate the effect of 875

non-depolarizing neuromuscular blockers (6). Recently magnesium sulphate was reported to reduce

anaesthetic requirements and shorten anaesthetic induction with propofol (7-9). It has potential

analgesic and sedative properties, therefore it may be used as adjuvant during general anesthesia

(10).

In this study our primary hypothesis was magnesium infusion has positive effects on awareness 880

under general anesthesia. Our secondary hypothesis was magnesium infusion can reduce pain at


/ 50


both intraoperative and postoperative period.

MATERIAL AND METHOD

After receiving hospital Clinical Trials Local Ethic Committee approval (reference Number: LUT-

10/60) and patients’ informed consent, 100 patients (American society of anesthesiologists status I-885

II and between 17-41 years old) undergoing cesarean section with general anesthesia were included

in the study. The study was conducted in accordance with the Helsinki declaration in Ankara

Hacettepe University Hospital between 2010-2011 and patient follow-up has been continued untill

2016 via phone calls. Patients with known history of magnesium sulphate hypersensivity,

hypermagnesemia, any degree of heart block, hypertension, diabetus mellitus, preterm or multiple 890

pregnancy, preoperative fetal distress or other medical conditions were excluded from the study. In

the operating room, electrocardiogram, non invasive blood pressure, peripheral oxygen saturation,

train of four (Datex-Ohmeda N-NMT Sensors) and bispectral index scoring (BIS) (Datex-Ohmeda

S/5TM) measurements were monitored. Patients were randomized into four groups by using a

computer-generated randomization schedule and each group included 25 patients. The study drug 895

solutions were prepared into 20-mL identical syringes for bolus doses and 500-mL serum

physiologic solutions for intraoperative infusions and labeled by an anesthetist who did not

participate in the study. The investigators and patients were blinded to group allocation. The first

and the second groups were planed to receive sevoflurane and desflurane as inhalation anesthetic

agent respectively. They were planed to receive serum physiologic in 20-mL syringes and serum 900

physiologic as infusion solution (Group S and D). In the third and fourth groups, patients were

planed to receive sevoflurane and desflurane as inhalation anesthetic agent respectively. They were

planed to receive 30 mg kg ֿ ֿ ¹ magnesium sulfate in 20-mL syringes and magnesium sulfate plus

serum physiologic as infusion solution (Group S-M and D-M).

Induction was performed with 2-3 mg kg ֿ ¹ i.v propofol and 0.6 mg kg ֿ ֿ i.v rocronium bromide in 905

all groups. After induction, in groups S-M and D-M, 30 mg kg ֿ ¹ i.v magnesium sulfate was

applied as bolus in 15-20 seconds and then 10 mg kg ֿ ֿ hour ֿ ¹ magnesium sulfate infusion in 500-


/ 50


mL serum physiologic solution was started.

At the maintenance of anesthesia 2% end-tidal sevoflurane and 4 lt min ֿ ֿ ֿ ¹ 40% O2-60% N2O

were used in group S and group S-M, and 6% end-tidal desflurane and 4 lt min ֿ ¹ 40% O2-60% 910

N2O were used in group D and group D-M. When heart rate or blood pressure increased more than

20% of baseline values, fentanyl 1 mcg kg ֿ ֿ ¹ was applied intravenously while minimum alveolar

concentration (MAC) remained constant. In all groups BIS values were recorded before induction,

right after induction and at five minute intervals throughout the operation. Intraoperative opioid

need was recorded following induction and throughout the operation. For postoperative analgesia, 915

1000 mg paracetamol was applied intravenously 15 minutes before the end of the surgery and 75

mg diclofenac sodium was applied at every 8 hours as rescue analgesic in the ward. Patients were

evaluated at the postoperative 1st , 2nd and 24th hours via Visual Analogue Scale (VAS).

Following anesthesia induction, a text chosen with the consultancy of Hacettepe University Medical

Faculty Psychiatry Department was listened to all patients via earphones. This text was a story 920

included in the “Wechsler Memory Scale” used for neurophysiological examination of the patients

and there were 24 key words in this single line text (11).

Similar to previous studies (12, 13), all patients were questioned about awareness under general

anesthesia at postoperative 1st, 6th, 24th hours, at the end of the 1st month by the same anesthesiogist.

As an addition to previous studies, we interviewed with the patients at the end of the first, second, 925

third, fourth and fifth year in order to evaluate long term effects of general anesthesia. First all

patients were given some clues about the story and then they were asked whether if they recalled

anything about the text or not. Besides Wechsler Memory Scale, questions from “Modified Brice

interviews” which is still accepted as the gold-standart for postoperative awareness screening were

also asked (14). The interview is consisted of five simple questions which were first defined by 930

Brice et al. (15) and then modified by Moerman et al. (16). These questions are listed as – “1) What

is the last thing you remember before sleeping? 2) What is the first thing you remember at awaking

after the surgery? 3) Do you remember anything in between? 4) Did you see any dreams? 5) What


/ 50


was the most disturbing thing you remember about the operation and anesthesia?.

STATISTICAL ANALYSIS 935

The statistical anaylsis was made by using the Statistical Package for Social Science, version 17.0

(SPSS Inc., Chicago, IL). All demographic datas and perioperative periods were evaluated with One

Way Variance Analysis. Turkey-HSD test was used for the multiple comparison between groups.

For evaluation of VAS values non-parametric Kruskal-Wallis test was performed. Exact chi-square

test was used to compare additional analgesic need, dreaming, remembering and recalling the story. 940

“P < 0,05” was accepted as statistically significant and all datas was defined as “mean±SD”.

RESULTS

A hundred and twenty patients were included into the study. Two of the patients excluded due to

intraoperative allergic symptoms. Six patients declined to participitate in the study postoperatively

and twelve patients excluded from the study due to intraoperative faults. The characteristics of 100 945

patients and surgery characteristics were similar in each group (Table 1). There was no significant

difference in the frequency of comorbidities between groups.

For analysis of BIS values, before induction (BIS 0), 5 minutes after the induction (BIS 5), total

operation median time (BIS Median) and end of operation (BIS End) time-points were chosen

(Table 2). 950

BIS values before the induction were similar in all groups (p > 0.05) whereas BIS values at BIS 5 is

significantly higher in the sevoflurane group (p < 0.001) (Figure 1). At the BIS Median point; BIS

values in Group S and Group D are similar to each other and statistically significantly higher than

the groups with magnesium infusion ( p < 0.001) (Figure 2). Likewise when BIS End values are

observed; Group S and Groups D were found to be similar to each other and significantly higher 955

than magnesium groups ( p < 0.001). There was no statistically significant difference amoung

magnesium groups ( p > 0.05). (Figure 3). BIS value ranges measured throughout the operation is

shown in Figure 4.

VAS scores were questioned at 1st, 2nd and 24th hour. VAS scores in all time points were


/ 50


significantly lower in magnesium groups (p < 0.05). VAS scores of group S and D were similar, 960

while groups S-M and D-M were similar to each other (Table 3).

Although intraoperative additional analgesic requirement was higher in non-magnesium groups, the

difference was not statistically significant (p = 0.307) (Table 4).

At the interviews performed at the end of 1st, 6th and 24th hour, one patient in groups S, two in group

D and one in group D-M were found to dream intraoperatively. They stated that their dreams were 965

not related to their surgeries. At the end of the first month, same four patients reported that they

dreamed intraoperatively but couldn’t remember anything about their dreams. This difference

amoung groups was not statistically significant (p > 0.05).

At the end of the first and second years we managed to interview with all patients and non of them

could remember anything new. At the end of the third, fouth and fifth years we couldn’t contact 970

with two patients in group S and three patients in each group S-M and group D-M. None of the

patients reported to hear any sound during the operation nor remember anything. None of the

patients could give a significant answer to the questions of Modified Brice interviews by means of

intraoperative awareness. Likewise, none of the patients could remember the story played through

earphones, or find any of the key words. None of the patients had any signs of posttraumatic stres 975

disorder meanwhile.

DISCUSSION

Our primary hypothesis was magnesium infusion has positive effects on awareness under general

anesthesia. We aimed to assess this effect by BIS measurements and postoperative interviews. In the

present study none of the patients had awareness under general anesthesia, while BIS scores were 980

significantly lower in groups with magnesium infusion.

Our secondary hypothesis was magnesium infusion can reduce pain at both intraoperative and

postoperative period. Although intraoperative opioid need was similar in all groups, VAS scores

were significantly lower in groups with magnesium infusion.

Awareness under general anesthesia is often experienced due to inadequate levels of anesthesia 985


/ 50


(17). It’s been reported in the literature that serious psycological problems which leads to

posttraumatic stress disorder may occur during long-term follow up of these patients (1). Today

intraoperative awareness is mostly observed when opioids and benzodiazepines or weak anesthetics

like nitrous oxide are used seperately or together. Contrary to this, inhalation anesthethics like

sevoflurane, desflurane, isoflurane and potent intravenous anesthetics used in proper concentrations 990

are believed to prevent intraoperative perception succesfully (18). However, there are plenty of

intraopertive awareness cases experienced with inhalation anesthetics in the literature (19, 20). In

the light of these informations, we suggest that adding an adjuvant agent to general anesthesia may

help preventing intraoperative awareness. In this study, we prefered to add magnesium infusion to

general anesthesia provided by sevoflurane or desflurane anesthetics and none of our patients 995

experienced awareness. Dreaming which is believed to be related with awareness was detected at

four patients but when we compared the groups by means of dreaming, there was no statistically

significant difference. Awareness under general anesthesia is a rare complication seen between

0.1%-0.2% of all patients (1). Some publications show that these numbers can rise upto 7-28% in

obstetric surgeries (1, 21, 22). Although the current study was held with obstetric patients, no one 1000

reported to experience awareness. The most likely reason is our sample size may lack to detect an

awareness case. Secondly constant and reasonable MAC values may prevent to see awareness under

general anesthesia.

In the study of Lee et al, different dosages of magnesium were compared with control group and it

was shown that BIS values were significantly lower in the groups with magnesium infusion (23). In 1005

the current study, BIS values were also significantly lower in the groups with magnesium infusion

througout the operation. This result supports our suggestion about magnesium being a good

advujant for general anesthesia. Beside this, BIS values of the groups with magnesium infusion

didn’t differ significantly. This brings the idea that magnesium may deepen the level of anesthesia

with regardless of type of inhalated anesthetic agent. On the other hand, when we look at the non-1010

magnesium groups; BIS values in the 5th minute after induction was higher in sevolfurane group


/ 50


than desflurane group. According to previous studies performed with similar inhalation anesthetics,

this difference between sevoflurane and desflurane is not suprising. It is known that different

inhalation anesthetics given at the end-tidal concentration levels providing same potency can result

in different BIS values of patients (24). Jellish et al. compared sevoflurane and desflurane effects 1015

and reported that BIS values were significantly lower in the desflurane group (25).

The analgesic effect mechanism of magnesium sulfate has not been shown clearly yet, but

inhibition of calcium channels and N-methyl-D-aspartate receptors are believed to have an

important role (26). In previous studies, bolus dosage of magnesium was shown to reduce

postoperative pain scores and additional analgesic need significantly (27, 28). Whereas, in 2001 Ko 1020

et al. reported that magnesium had no effect on postoperative pain in their study. They claimed that

even in increased serum concentrations, magnesium slightly passes the blood-brain barrier, so

intravenous magnesium has minimal effect on postoperative pain (29). In the current study, contrary

to Ko et al. we found VAS scores of magnesium groups were significantly lower at all time points.

Nowadays magnesium is in the focus of studies analyzing post operative inflammation. It was 1025

recently reported to reduce postoperative sore throat significantly (30).

The major limitation of our study is the relatively small sample size. In order to get more objective

data on awareness under general anesthesia, it’s necessary to perform studies with larger number of

patients but nowadays it’s becoming harder due to increased ratios of regional anesthesia at

cesarean sections. 1030

CONCLUSION

In this study, although magnesium infusion didn’t make a significant difference on awareness under

general anesthesia, it provided lower intraoperative BIS and postoperative VAS values. Therefore,

we believe that magnesium infusion in cesarean section can be useful by reducing patients’ 1035

inoperative anesthetic and postoperative analgesic need and prevent depressant effects on fetus.


/ 50


1040

REFERENCES

1. Ghoneim MM, Block RI, Haffarnan M, Mathews MJ. Awareness during anesthesia: risk 1045

factors, causes and sequelae: a review of reported cases in the literature. Anesth Analg. 2009 Feb;108(2):527-35. PubMed PMID: 19151283. Epub 2009/01/20. eng.

2. Lopez U, Habre W, Van der Linden M, Iselin-Chaves IA. Intra-operative awareness in children and post-traumatic stress disorder. Anaesthesia. 2008 May;63(5):474-81. PubMed PMID:

18412644. Epub 2008/04/17. eng. 1050

3. Osterman JE, Hopper J, Heran WJ, Keane TM, van der Kolk BA. Awareness under anesthesia and the development of posttraumatic stress disorder. Gen Hosp Psychiatry. 2001 Jul-Aug;23(4):198-204. PubMed PMID: 11543846. Epub 2001/09/07. eng. 4. Campbell J, Sultan P. Regional anaesthesia for caesarean section: a choice of three techniques. Br J Hosp Med (Lond). 2009 Oct;70(10):605. PubMed PMID: 19966715. 1055

5. Sebel PS, Bowdle TA, Ghoneim MM, Rampil IJ, Padilla RE, Gan TJ, et al. The incidence of

awareness during anesthesia: a multicenter United States study. Anesth Analg. 2004 Sep;99(3):833-9, table of contents. PubMed PMID: 15333419. Epub 2004/08/31. eng.

6. James MF, Beer RE, Esser JD. Intravenous magnesium sulfate inhibits catecholamine release associated with tracheal intubation. Anesthesia and analgesia. 1989 Jun;68(6):772-6. PubMed 1060

PMID: 2735543. 7. Gupta K, Vohra V, Sood J. The role of magnesium as an adjuvant during general anaesthesia.

Anaesthesia. 2006 Nov;61(11):1058-63. PubMed PMID: 17042843. Epub 2006/10/18. eng. 8. Altan A, Turgut N, Yildiz F, Turkmen A, Ustun H. Effects of magnesium sulphate and

clonidine on propofol consumption, haemodynamics and postoperative recovery. Br J Anaesth. 1065

2005 Apr;94(4):438-41. PubMed PMID: 15653705. Epub 2005/01/18. eng.

9. Telci L, Esen F, Akcora D, Erden T, Canbolat AT, Akpir K. Evaluation of effects of magnesium sulphate in reducing intraoperative anaesthetic requirements. Br J Anaesth. 2002 Oct;89(4):594-8. PubMed PMID: 12393361. Epub 2002/10/24. eng. 10. Barbosa FT, Barbosa LT, Juca MJ, Cunha RM. Applications of magnesium sulfate in obstetrics 1070

and anesthesia. Rev Bras Anestesiol. 2010 Jan-Feb;60(1):104-10. PubMed PMID: 20169270. Epub

2010/02/20. eng por.

11. Shaygannejad V, Janghorbani M, Ashtari F, Zanjani HA, Zakizade N. Effects of rivastigmine on memory and cognition in multiple sclerosis. Can J Neurol Sci. 2008 Sep;35(4):476-81. PubMed 1075

PMID: 18973065. Epub 2008/11/01. eng. 12. Myles PS, Leslie K, McNeil J, Forbes A, Chan MT. Bispectral index monitoring to prevent

awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet. 2004 May 29;363(9423):1757-63. PubMed PMID: 15172773. Epub 2004/06/03. eng.


/ 50


13. Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M. Effect of 1080

epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung

ventilation. Acta Anaesthesiol Scand. 2010 Jul;54(6):703-9. PubMed PMID: 20085547. Epub 2010/01/21. eng.

14. Sneyd JR, Mathews DM. Memory and awareness during anaesthesia. Br J Anaesth. 2008 Jun;100(6):742-4. PubMed PMID: 18483111. Epub 2008/05/17. eng. 1085

15. Brice DD, Hetherington RR, Utting JE. A simple study of awareness and dreaming during anaesthesia. Br J Anaesth. 1970 Jun;42(6):535-42. PubMed PMID: 5423844. Epub 1970/06/01. eng.

16. Moerman N, Bonke B, Oosting J. Awareness and recall during general anesthesia. Facts and feelings. Anesthesiology. 1993 Sep;79(3):454-64. PubMed PMID: 8363069. Epub 1993/09/01. eng.

17. Ghoneim MM. Awareness during anesthesia. Anesthesiology. 2000 Feb;92(2):597-602. 1090

PubMed PMID: 10691248. Epub 2000/02/26. eng.

18. Guler T. İntraoperatif Uyanıklık. Türk Anesteziyoloji ve Reanimasyon Derneği Dergisi 2009;37(5):265-79. 19. Kino A KR, Wakamatsu T, Hashiguchi M, Nakamura K. Awareness during anesthesia with sevoflurane: a case report. Masui The Japanese journal of anesthesiology. 2006;55(10):1250-2. 1095

20. Kino A NK. Awareness during general anesthesia for head and neck surgery--a case report. Masui The Japanese journal of anesthesiology. 2011;60(2):241-3. 21. Paech MJ, Scott KL, Clavisi O, Chua S, McDonnell N. A prospective study of awareness and recall associated with general anaesthesia for caesarean section. Int J Obstet Anesth. 2008 Oct;17(4):298-303. PubMed PMID: 18617387. Epub 2008/07/12. eng. 1100

22. Crawford JS. Awareness during operative obstetrics under general anaesthesia. Br J Anaesth. 1971 Feb;43(2):179-82. PubMed PMID: 5550849. Epub 1971/02/01. eng.

23. Lee DH, Kwon IC. Magnesium sulphate has beneficial effects as an adjuvant during general anaesthesia for Caesarean section. Br J Anaesth. 2009 Dec;103(6):861-6. PubMed PMID:

19783538. Epub 2009/09/29. eng. 1105

24. Samarkandi AH. The bispectral index system in pediatrics--is it related to the end-tidal

concentration of inhalation anesthetics? Middle East J Anesthesiol. 2006 Feb;18(4):769-78. PubMed PMID: 16749571. Epub 2006/06/06. eng.

25. Jellish WS, Owen K, Edelstein S, Fluder E, Leonetti JP. Standard anesthetic technique for middle ear surgical procedures: a comparison of desflurane and sevoflurane. Otolaryngol Head 1110

Neck Surg. 2005 Aug;133(2):269-74. PubMed PMID: 16087026. Epub 2005/08/10. eng. 26. Miranda HF, Bustamante D, Kramer V, Pelissier T, Saavedra H, Paeile C, et al. Antinociceptive effects of Ca2+ channel blockers. Eur J Pharmacol. 1992 Jul 7;217(2-3):137-41. PubMed PMID: 1425934. Epub 1992/07/07. eng. 27. Gupta SD MK, Mukherjee M, Roy S, Sarkar A, Kundu S, et al. Effect of magnesium infusion 1115

on thoracic epidural analgesia. Saudi journal of anaesthesia. 2011;5(1):55-61. 28. Kiran S GR, Verma D. Evaluation of a single-dose of intravenous magnesium sulphate for prevention of postoperative pain after inguinal surgery. Indian journal of anaesthesia. 2011;55(1):31-5.

29. Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS. Magnesium sulfate does not reduce 1120

postoperative analgesic requirements. Anesthesiology. 2001 Sep;95(3):640-6. PubMed PMID:

11575536. Epub 2001/09/29. eng. 30. Yadav M CN, Gopinath R. Effect of magnesium sulfate nebulization on the incidence of

postoperative sore throat. Journal of anaesthesiology, clinical pharmacology. 2016;32(2):168-71. 1125 There is no conflict of interest.


/ 50


1130

TABLES: 1135



Table 2. BIS at Different Time-Points Amoung Groups 1140

1145

*BIS: bispectral index score, sevo: sevoflurane, des: desflurane, mg: magnesium sulphate, SD:

standart deviation, BIS Med: BIS at the medium point of operation

Sevo. Sevo + Mg Des. Des + Mg Total

Age (Year) 29.7 ± 5.1 30.2 ± 5.8 30.2 ± 4.3 29.7 ± 4.78 29.97 ± 4.97

Weight (kg) 73.4 ± 14.7 77.5 ± 11.8 79.9 ± 14.7 77.1 ± 14 77.0 ± 13.7

Operation time

(min)

47.4 ± 11.19 44.8 ± 7.96 47.6 ± 10.7 4.4 ± 9.6 45.3 ± 10.1

Group BIS 0 BIS 5 BIS Med BIS End

sevo Mean 95.9 50.8 55.6 64.8

SD 2.76 7.8 6.08 7.5

sevo+mg Mean 95.3 39.2 40.9 53.0

SD 2.88 10.5 7.4 8.2

des Mean 95.2 38.96 52.6 62.88

SD. 3.05 6.5 7.1 4.5

des+mg Mean 96.28 35.96 41.1 50.88

SD 2.4 10.1 9.78 8.3


/ 50


1150

1155

1160

Tablo 3. VAS scores amoung groups

Group VAS1 VAS2 VAS24

sevo Mean 8.16 5.12 4.00

N 25 25 25

SD .898 .666 .6455

des Mean 8.12 4.88 3.80

N 25 25 25

SD .833 .881 .707

sevo+mg Mean 7.16 3.52 3,00

N 25 25 25

SD .624 .653 .645

des+mg Mean 7.12 3.56 3.00

N 25 25 25

SD .600 .651 .408

*Sevo: sevoflurane, des: desflurane, mg: magnesium sulphate, SD: standart deviation, VAS1: VAS

score at postoperative first hour, VAS2: VAS score at postoperative second hour, VAS24: VAS score

at postoperative 24th hour

1165

Table 4. Intraoperative Additional Analgesic Requirement

Group

Total sevo des sevo+mg des+mg

fentanyl yes 15 14 9 11 49

no 10 11 16 14 51

Total 25 25 25 25 100


/ 50


Sevo: sevoflurane, des: desflurane, mg: magnesium sulphate

1170

Figure 1. BIS Values Among Groups at 5 Minutes After the Induction

*sevo; sevoflurane, des; desflurane, mg; magnesium sulphate, BIS; bispectral index, SD; Standard

deviation

Figure 2. BIS Values Among Groups at BIS Median Point 1175


deviation


/ 50


At the BIS Median point; BIS values in Group S and Group D are similar to each other and

statistically significantly higher than the groups with magnesium ( p < 0.001) 1180

Figure 3. BIS Values Among Groups at BIS End Point


deviation

BIS values of group S and group D at the end of the operation were similar to each other and 1185

significantly higher than magnesium groups ( p < 0.001). There was no statistically significant

difference amoung magnesium groups ( p > 0.05)


1190 Sevo; sevoflurane, des; desflurane, mg; magnesium sulphate, BIS; bispectral index


/ 50



/ 50


Kaynaklar References

Kayıt Tarihi: 08.09.2016 23:59:36 1195

REFERENCES

1. Ghoneim MM, Block RI, Haffarnan M, Mathews MJ Awareness during anesthesia: risk

factors, causes and sequelae: a review of reported cases in the literature. Anesth Analg 1200

2009, 108(2):527-35.

2. Lopez U, Habre W, Van der Linden M, Iselin-Chaves IA Intra-operative awareness in children and post-traumatic stress disorder. Anaesthesia 2008, 63(5):474-81.

3. Osterman JE, Hopper J, Heran WJ, Keane TM, van der Kolk Awareness under anesthesia and

the development of posttraumatic stress disorder. Gen Hosp Psychiatry 2001, 23(4):198-1205

204.

4. Campbell J, Sultan P Regional anaesthesia for caesarean section: a choice of three techniques. Br J Hosp Med (Lond) 2009, 70(10):605.

5. Sebel PS, Bowdle TA, Ghoneim MM, Rampil IJ, Padilla RE, Gan TJ, et al. The incidence of awareness during anesthesia: a multicenter United States study. Anesth Analg 2004, 1210

99(3):833-9 6. James MF, Beer RE, Esser JD Intravenous magnesium sulfate inhibits catecholamine release

associated with tracheal intubation. Anesth analg 1989, 68(6):772-6 7. Gupta K, Vohra V, Sood J The role of magnesium as an adjuvant during general anaesthesia.

Anaesthesia 2006, 61(11):1058-63. 1215

8. Altan A, Turgut N, Yildiz F, Turkmen A, Ustun H Effects of magnesium sulphate and clonidine

on propofol consumption, haemodynamics and postoperative recovery. Br J Anaesth 2005, 94(4):438-41.

9. Telci L, Esen F, Akcora D, Erden T, Canbolat AT, Akpir K Evaluation of effects of magnesium sulphate in reducing intraoperative anaesthetic requirements. Br J Anaesth 2002, 1220

89(4):594-8.

10. Barbosa FT, Barbosa LT, Juca MJ, Cunha RM Applications of magnesium sulfate in obstetrics and anesthesia. Rev Bras Anestesiol 2010, 60(1):104-10.

11. Shaygannejad V, Janghorbani M, Ashtari F, Zanjani HA, Zakizade N Effects of rivastigmine on memory and cognition in multiple sclerosis. Can J Neurol Sci 2008, 35(4):476-81. 1225

12. Myles PS, Leslie K, McNeil J, Forbes A, Chan MT Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004,

363(9423):1757-63. 13. Elhakim M, Abdelhamid D, Abdelfattach H, Magdy H, Elsayed A, Elshafei M Effect of

epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-1230

lung ventilation. Acta Anaesthesiol Scand 2010, 54(6):703-9.

14. Sneyd JR, Mathews DM Memory and awareness during anaesthesia. Br J Anaesth 2008, 100(6):742-4.

15. Brice DD, Hetherington RR, Utting JE A simple study of awareness and dreaming during anaesthesia. Br J Anaesth 1970, 42(6):535-42. 1235

16. Moerman N, Bonke B, Oosting J Awareness and recall during general anesthesia. Facts and feelings. Anesthesiology 1993, 79(3):454-64.

17. Ghoneim MM Awareness during anesthesia. Anesthesiology 2000, 92(2):597-602. 18. Guler T İntraoperatif Uyanıklık. Turk J Anesthesiol Reanim 2009, 37(5):265-79. 19. Kino A KR, Wakamatsu T, Hashiguchi M, Nakamura K Awareness during anesthesia with 1240

sevoflurane: a case report. Masui The Japanese journal of anesthesiology 2006,


/ 50


55(10):1250-52. 20. Kino A NK: Awareness during general anesthesia for head and neck surgery--a case report.

Masui The Japanese journal of anesthesiology 2011, 60(2):241-3. 21. Paech MJ, Scott KL, Clavisi O, Chua S, McDonnell N A prospective study of awareness and 1245

recall associated with general anaesthesia for caesarean section. Int J Obstet Anesth 2008, 17(4):298-303.

22. Crawford JS Awareness during operative obstetrics under general anaesthesia. Br J Anaesth 1971, 43(2):179-82.

23. Lee DH, Kwon IC Magnesium sulphate has beneficial effects as an adjuvant during general 1250

anaesthesia for Caesarean section. Br J Anaesth 2009, 103(6):861-6.

24. Samarkandi AH The bispectral index system in pediatrics--is it related to the end-tidal concentration of inhalation anesthetics? Middle East J Anesthesiol 2006, 18(4):769-78.

25. Jellish WS, Owen K, Edelstein S, Fluder E, Leonetti JP Standard anesthetic technique for middle ear surgical procedures: a comparison of desflurane and sevoflurane. Otolaryngol 1255

Head Neck Surg 2005, 133(2):269-74. 26. Miranda HF, Bustamante D, Kramer V, Pelissier T, Saavedra H, Paeile C, et al. Antinociceptive

effects of Ca2+ channel blockers. Eur J Pharmacol 1992, 217(2-3):137-41. 27. Gupta SD, Mitra K, Mukherjee M, Roy S, Sarkar A, Kundu S, et al.: Effect of magnesium

infusion on thoracic epidural analgesia. Saudi journal of anaesthesia 2011, 5(1):55-61. 1260

28. Kiran S GR, Verma D Evaluation of a single-dose of intravenous magnesium sulphate for prevention of postoperative pain after inguinal surgery. Indian journal of anaesthesia 2011,

55(1):31-5. 29. Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS: Magnesium sulfate does not reduce

postoperative analgesic requirements. Anesthesiology 2001, 95(3):640-6. 1265

30. Yadav M CN, Gopinath R Effect of magnesium sulfate nebulization on the incidence of


1270


/ 50


Tablolar Tables

Kayıt Tarihi: 09.09.2016 11:15:36

1275

TABLES:



1280

Table 2. BIS at Different Time-Points Amoung Groups

1285

*BIS: bispectral index score, sevo: sevoflurane, des: desflurane, mg: magnesium sulphate, SD:

standart deviation, BIS Med: BIS at the medium point of operation 1290

1295

1300

Sevo. Sevo + Mg Des. Des + Mg Total

Age (Year) 29.7 ± 5.1 30.2 ± 5.8 30.2 ± 4.3 29.7 ± 4.78 29.97 ± 4.97

Weight (kg) 73.4 ± 14.7 77.5 ± 11.8 79.9 ± 14.7 77.1 ± 14 77.0 ± 13.7

Operation time

(min)

47.4 ± 11.19 44.8 ± 7.96 47.6 ± 10.7 4.4 ± 9.6 45.3 ± 10.1

Group BIS 0 BIS 5 BIS Med BIS End

sevo Mean 95.9 50.8 55.6 64.8

SD 2.76 7.8 6.08 7.5

sevo+mg Mean 95.3 39.2 40.9 53.0

SD 2.88 10.5 7.4 8.2

des Mean 95.2 38.96 52.6 62.88

SD. 3.05 6.5 7.1 4.5

des+mg Mean 96.28 35.96 41.1 50.88

SD 2.4 10.1 9.78 8.3


/ 50


Tablo 3. VAS scores amoung groups

Group VAS1 VAS2 VAS24

sevo Mean 8.16 5.12 4.00

N 25 25 25

SD .898 .666 .6455

des Mean 8.12 4.88 3.80

N 25 25 25

SD .833 .881 .707

sevo+mg Mean 7.16 3.52 3,00

N 25 25 25

SD .624 .653 .645

des+mg Mean 7.12 3.56 3.00

N 25 25 25

SD .600 .651 .408

*Sevo: sevoflurane, des: desflurane, mg: magnesium sulphate, SD: standart deviation, VAS1: VAS

score at postoperative first hour, VAS2: VAS score at postoperative second hour, VAS24: VAS score

at postoperative 24th hour 1305

Table 4. Intraoperative Additional Analgesic Requirement

Group

Total sevo des sevo+mg des+mg

fentanyl yes 15 14 9 11 49

no 10 11 16 14 51

Total 25 25 25 25 100

Sevo: sevoflurane, des: desflurane, mg: magnesium sulphate

1310


/ 50


Resimler Figures

Kayıt Tarihi: 09.09.2016 11:16:01

1315 Figure 1. BIS Values Among Groups at 5 Minutes After the Induction


deviation

Figure 2. BIS Values Among Groups at BIS Median Point 1320


deviation

At the BIS Median point; BIS values in Group S and Group D are similar to each other and

statistically significantly higher than the groups with magnesium ( p < 0.001) 1325

Figure 3. BIS Values Among Groups at BIS End Point


/ 50



deviation

BIS values of group S and group D at the end of the operation were similar to each other and 1330

significantly higher than magnesium groups ( p < 0.001). There was no statistically significant

difference amoung magnesium groups ( p > 0.05)


1335 Sevo; sevoflurane, des; desflurane, mg; magnesium sulphate, BIS; bispectral index


/ 50


Diğer Dosyalar Flowchart 1340 Kayıt Tarihi: 09.09.2016 00:00:12

1345

Assessed for eligibility (n=120 )

Excluded (n=20 ) Not meeting inclusion criteria (n= 4 ) Declined to participate (n=6 )

Other reasons (n=10 )

Analysed (n=23 )

Excluded from analysis

(n=0)

Lost to follow-up (n= 2)

Group S (n=25)

Received Sevoflurane

(n=25)

Lost to follow-up (n=3 )

Group D-M (n=25)

Received Desflurane

and Magnesium

(n=25)

Analysed (n=22 )


(n=0 )

Allocation

Analysis

Follow-Up

Randomized (n= 100 )

Enrollment

Group D (n=25 )

Received Desflurane

(n=25)

Group S-M (n=25 )

Received

Sevoflurane and Magnesium (n=25)

Lost to follow-up (n= 0) Lost to follow-up (n= 3)

Analysed (n=25 )


(n=0)

Analysed (n=22 )


(n=0)


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